Our goal is to understand molecular pathogenesis of FUS proteinopathy and related dementia. This is a group of neurological disorders characterized by the presence of FUS-positive inclusion bodies, including frontotemporal lobar degeneration (FTLD), related dementias and motor neuron diseases. FUS interacts genetically or biochemically with a number of genes associated with Alzheimer's disease (AD), including tau and TDP-43. Although function of FUS in DNA repair, transcription regulation or stress granule formation has been documented, the role of FUS in mitochondria, especially in mitochondrial stress response, remains unclear. Among different mechanisms, mitochondrial impairment is well-established for AD pathogenesis. However, only recently, has it been suggest that mitochondrial dysfunction is a critical early event in FUS-associated neurodegeneration. Targeting mitochondrial damage may provide a new avenue for development of new therapies against dementia associated with FUS and other RNA binding proteins (RBPs). Published work and our preliminary data led to the hypotheses that FUS may play an important role in regulating mitochondrial stress response (MSR), and that mitochondrial damage and dysfunctional MSR contribute to the pathogenesis of FUS proteinopathy and related dementia. MSR signature of Alzheimer's disease has been recently reported, however, little is known about MSR in FUS proteinopathy. Our preliminary study has revealed a previously unknown role of FUS in regulating MSR. We plan to use a combined molecular, biochemical, imaging and genetic approach together with cellular, animal models as well as patient samples and patient-derived neurons to dissect mechanisms underlying mitochondrial damage and neurodegeneration in FUS proteinopathy. We propose three inter-related aims. In Aim 1, we will determine the role of FUS in mitochondrial damage and in regulating MSR. In Aim 2, we will identify genetic modifier genes using our fly model and characterize candidate FUS target genes in the rat model of FUS proteinopathy. In Aim 3, we will determine if mitochondrial damage and dysregulated MSR are shared features in FTLD-FUS and ALS-FUS and test whether genetically correcting mutation(s) in patient iPSCs can ameliorate mitochondrial damage and neurodegenerative phenotypes in patient neurons. Successful completion of our proposed study will not only help elucidate molecular mechanisms underlying dementias associated with FUS and other RBP genes associated with AD, but also identify potential therapeutic targets for improving clinical outcomes of these devastatingdiseases.